Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia

ABSTRACT

This invention provides compounds of Formula I having the structure  
                 
 
     R 1  is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,  
                 
 
     R 2  is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms;  
     R 3  and R 4  are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR 7 (CH 2 ) m CO 2 H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur;  
     R 5  is hydrogen, alkyl of 1-6 carbon atoms, —CH(R 8 )R 9 , —C(CH 2 ) n CO 2 R 10 , —C(CH 3 ) 2 CO 2 R 10 , —CH(R 8 )(CH 2 ) n CO 2 R 10 , —CH(R 8 )C 6 H 4 CO 2 R 10 , or —CH 2 -tetrazole;  
     R 6  is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms;  
     R 7  is hydrogen or alkyl of 1 to 6 carbon atoms;  
     R 8  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,  
                 
 
     R 9  is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ;  
     R 10  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;  
     R 11  is alkylene of 1 to 3 carbon atoms;  
     R 12  is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;  
     X is O, or S;  
     Y is O, N, or S;  
     Z is C, or N;  
     Q is O, N, or S;  
     m=1-3;  
     n=1-6,  
     or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/113,661, which was converted from U.S. patentapplication Ser. No. 09/076,710, filed May 12, 1998, pursuant to apetition filed under 37 C.F.R. 1.53(c)(2)(i) on Jul. 6, 1998.

BACKGROUND OF THE INVENTION

[0002] The prevalence of insulin resistance in glucose intolerantsubjects has long been recognized. Reaven et al (American Journal ofMedicine 1976, 60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

[0003] Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

[0004] The association of hyperinsulinemia with obesity and withischemic diseases of the large blood vessels (e.g. atherosclerosis) hasbeen well established by numerous experimental, clinical andepidemiological studies (summarized by Stout, Metabolism 1985, 34, 7,and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987,3, 463). Statistically significant plasma insulin elevations at 1 and 2hours after oral glucose load correlates with an increased risk ofcoronary heart disease.

[0005] Since most of these studies actually excluded diabetic subjects,data relating the risk of atherosclerotic diseases to the diabeticcondition are not as numerous, but point in the same direction as fornondiabetic subjects (Pyorala et al). However, the incidence ofatherosclerotic diseases in morbidity and mortality statistics in thediabetic population exceeds that of the nondiabetic population (Pyoralaet al; Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al,Mortality from diabetes, in Diabetes in America 1985).

[0006] The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

[0007] It is now appreciated that insulin resistance is usually theresult of a defect in the insulin receptor signaling system, at a sitepost binding of insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

[0008] Protein-tyrosine phosphatases (PTPases) play an important role inthe regulation of phosphorylation of proteins. The interaction ofinsulin with its receptor leads to phosphorylation of certain tyrosinemolecules within the receptor protein, thus activating the receptorkinase. PTPases dephosphorylate the activated insulin receptor,attenuating the tyrosine kinase activity. PTPases can also modulatepost-receptor signaling by catalyzing the dephosphorylation of cellularsubstrates of the insulin receptor kinase. The enzymes that appear mostlikely to closely associate with the insulin receptor and therefore,most likely to regulate the insulin receptor kinase activity, includePTP1B, LAR, PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B.J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

[0009] McGuire et al. (Diabetes 1991, 40, 939), demonstrated thatnondiabetic glucose intolerant subjects possessed significantly elevatedlevels of PTPase activity in muscle tissue vs. normal subjects, and thatinsulin infusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

[0010] Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

[0011] The compounds of this invention have been shown to inhibitPTPases derived from rat liver microsomes and human-derived recombinantPTPase-1B (hPTP-1B) in vitro. They are useful in the treatment ofinsulin resistance associated with obesity, glucose intolerance,diabetes mellitus, hypertension and ischemic diseases of the large andsmall blood vessels.

DESCRIPTION OF THE INVENTION

[0012] This invention provides a compound of formula I having thestructure

[0013] R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,thienyl, furyl, pyridyl,

[0014] R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10carbon atoms;

[0015] R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino,carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide,—NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, orheterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatomsselected from oxygen, nitrogen, or sulfur;

[0016] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹,—C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹°, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰,—CH(R⁸)C₆H₄CO₂R¹⁰, or —CH₂-tetrazole;

[0017] R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxyof 1-6 carbon atoms;

[0018] R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms;

[0019] R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbonatoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms,phthalic acid,

[0020] R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²;

[0021] R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbonatoms, aralkyl of 7-15 carbon atoms;

[0022] R¹¹ is alkylene of 1 to 3 carbon atoms;

[0023] R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbonatoms, aralkyl of 7-15 carbon atoms;

[0024] X is O, or S;

[0025] Y is O, N, or S;

[0026] Z is C, or N;

[0027] Q is O, N, or S;

[0028] m=1-3;

[0029] n=1-6,

[0030] or a pharmaceutically acceptable salt thereof, which are usefulin treating metabolic disorders related to insulin resistance orhyperglycemia.

[0031] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, preferably alkali metal salts, for example,sodium, lithium, or potassium, when a compound of this inventioncontains a carboxylate or phenolic moiety, or similar moiety capable offorming base addition salts.

[0032] Alkyl includes both straight chain as well as branched moieties.Halogen means bromine, chlorine, fluorine, and iodine. It is preferredthat the aryl portion of the aryl or aralkyl substituent is a phenyl,naphthyl or 1,4-benzodioxan-5-yl group; with phenyl being mostpreferred. The aryl moiety may be optionally mono-, di-, ortri-substituted with a substituent selected from the group consisting ofalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl,halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbonatoms, and dialkylamino in which each of the alkyl groups is of 1-6carbon atoms, nitro, cyano, —CO₂H, alkylcarbonyloxy of 2-7 carbon atoms,and alkylcarbonyl of 2-7 carbon atoms.

[0033] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable-salts thereof.

[0034] Preferred compounds of this invention are those compounds ofFormula I, X is oxygen. More preferred compouds of this invention arethose compounds of of Formula I, wherein:

[0035] X is 0;

[0036] R¹ is phenyl substituted with R⁶;

[0037] R² is alkyl of 1-6 carbon atoms; and

[0038] R³ and R⁴ are each, independently, hydrogen or halogen.

[0039] Specifically preferred compounds of the present invention are setforth below:

[0040]4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0041]4-(4′-methoxy-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0042]4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0043]3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0044]{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0045]{3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0046]2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4yloxy}-3-phenyl-propionic acid

[0047]2-{3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid

[0048]3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0049]{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0050]2-{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid methyl ester

[0051]2-{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid

[0052]2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione

[0053]2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-3-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione

[0054]5-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxymethyl}-1H-tetrazole

[0055] or a pharmaceutically acceptable salt thereof.

[0056] The compounds of this invention were be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using to literature procedures.These Schemes show the preparation of representative compounds of thisinvention.

[0057] In Scheme I commercially available ketones (1) were treated withhydroxylamine in the presence of sodium acetate to produce oximes (2).Oximes (2) were converted to oxazoles by a known methodology [ref. Tet.Lett. 1980, 21, 2359-2360], where oximes (2) were treated with acetylchlorides in the presence of pyridine to produce oxazoles (3). Oxazoles(3) were coupled with aryl boronic acids of general structure (4; R³, R⁴are alkyl, aryl, trifluoromethyl, substituted aryl, nitro, carbocyclic 5to 7 carbon atoms rings or heterocyclic rings 5 to 7 atom rings withfrom 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur)using the Suzuki protocol [ref. Syn. Comm. 1981, 11, 513-519] to producebiphenyls (5). The aryl boronic acids are either commercially availableor can be prepared according to known methodology [ref. J. Org. Chem,1984, 49, 5237-5243]. Biphenyls (5) converted to phenols (6) bytreatment with boron tribromide in dichloromethane [ref. J. Org. Chem.1974, 39, 1427-1429]. Phenols (6)

[0058] were alkylated with bromo or chloro-alkylcarboxylates [(Br orCl)(CH₂)_(n)CO₂R¹²] in the presence of sodium hydride or potassiumcarbonate, using dimethylformamide or acetonitrile as the solvent.Subsequent saponification with sodium hydroxide in methyl alcohol andtetrahydrofuran produced biphenyls (7). Coupling of biphenyls (6) withhydroxy-alkyl-carboxylates [HOCH(R⁸)CO₂R¹²] using the Mitsunobu protocol[ref. Synthesis. 1981, 1-27], followed by saponification with sodiumhydroxide in methyl alcohol and tetrahydrofuran produced biphenyls (8).Tetrazoles (9) were prepared from phenols (6) in a two step sequence.First the phenols (6) were alkylated with bromoacetonitrile in thepresence of sodium hydride, and secondly, the nitrile was converted totetrazoles (9) with sodium azide.

[0059] In Scheme II thiazoles (10) were brominated with bromine in thepresence of sodium acetate. The 4-bromo-thiazoles (11) were coupled with4,4′-methoxy biphenyl boronic acid using the Suzuki protocol [ref. Syn.Comm. 1981, 11, 513-519] to give biphenyls (12). Biphenyls (12) werefurther converted to the desired products in substantially the samemanner as described in Scheme I.

[0060] In Scheme III, the biphenyl compounds (13) can be monobrominatedor dibrominated using bromine, potassium acetate and acetic acid. Oneequivalent of bromine in a high dilution reaction mixture and lowtemperatures in the range of 5-10° C. afforded predominantly themonobrominated product (14; R³, R⁴═H, Br). The dibrominated product (14;R³, R⁴=Br, Br) was obtained with two equivalents of bromine at roomtemperature. The Suzuki coupling protocol [ref. Syn. Comm. 1981, 11,513-519] was used to generate the terphenyls 15 and 16. Coupling of themonobromo compounds (14; R³, R⁴═H, Br) with boronic acids R¹³—Ar—B(OH)₂;(R¹³=halogen, trifluoromethyl, alkoxy, alkyl, nitro, amino, carboalkoxy)in the present of an inorganic base, for example KCO₃, or Ba(OH)₂, andpalladium (0 or II) catalyst, for example Pd(PPh3)₄, Pd(OAc)₂, or(dppf)PdCl₂, produced terphenyls (15; R³═H). Similarly, the dibromocompounds (14; R³, R⁴=Br, Br) can undergo Suzuki coupling to affordeither the di-coupled product (16) by using 2 equivalents of boronicacid at high temperatures (100° C.), or the mono-coupled-mono-bromoproduct (15; R³, R⁴=Br, Aryl-R¹³). Both the bromo and dibromo compoundscan afford in the same synthetic manner products with variousheterocyclic boronic acids, for example thiophene, furan, oxazole,thiazole, pyridine.

[0061] In Scheme IV oxazoles (3) were coupled with aryl boronic acids ofgeneral structure (4; R³, R⁴ are alkyl, aryl, trifluoromethyl,substituted aryl, nitro, carbocyclic 5 to 7 carbon atoms rings orheterocyclic rings 5 to 7 atom rings with from 1 to 3 heteroatomsselected from oxygen, nitrogen, and sulfur) using the Suzuki protocol[ref. Syn. Comm. 1981, 11, 513-519] to produce biphenyls (17). Biphenyls(17) were converted to oximes (18) with hydroxylamine in the presence ofsodium acetate. Oximes (18) were reduced with sodium cyanoborohydrideunder acidic conditions to produce to hydroxylamines (19). Thehydroxylamines (19) were treated with N-chlorocarbonyl)isocyanate toproduce oxadiazolidinediones (20). Thiazolidinediones were prepared frombenzaldehydes (17) using known methodology [ref. J. Med. Chem., 1992,35, 1853-1864].

[0062] The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

[0063] The ability of compounds of this invention to treat or inhibitdisorders related to insulin resistance or hyperglycemia was establishedwith representative compounds of this invention in the following twostandard pharmacological test procedures which measure the inhibition ofPTPase.

[0064] Inhibition of Tri-Phosphorylated Insulin ReceptorDodecaphosphopeptide Dephosphorylation by Rat Hepatic 2Rotein-TyrosinePhosphatases (PTPases)

[0065] This standard pharmacological test procedure assess theinhibition of rat hepatic microsomal PTPase activity using, assubstrate, the phosphotyrosyl dodecapeptide corresponding to the1142-1153 insulin receptor kinase domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues. The procedure used and results obtainedare briefly outlined below.

[0066] Preparation of Microsomal Fraction: Rats (Male Sprague-Dawleyrats (Charles River, Kingston, N.Y.) weighing 100-150 g, maintained onstandard rodent chow (Purina)) are sacrificed by asphyxiation with CO₂and bilateral thoracotomy. The liver is removed and washed in cold 0.85%(w/v) saline and weighed. The tissue is homogenized on ice in 10 volumesof Buffer A and the microsomes are isolated essentially as described byMeyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR.Vanadate normalizes hyperglycemia in two mouse models ofnon-insulin-dependent diabetes mellitus. J Clin Invest 1991;87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD, editors. Molecular biology of the cell. New York: Garland Publishing,Inc., 1989 with minor modifications. The liver homogenate is filteredthrough silk to remove any remaining tissue debris and then iscentrifuged at 10,000×g for 20 minutes at 40 C. The supernatant isdecanted and centrifuged at 100,000×g for 60 minutes at 40 C. Thepellet, microsomes and small vesicles, is resuspended and lightlyhomogenized in: 20 mM TRIS-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mMsucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK,0.5 mM benzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H₅Bantipain, 5 ug/ml chymostatin, 10 ug/ml aprotinin (Buffer A), to a finalconcentration of approximately 850 ug protein/ml. Protein concentrationis determined by the Pierce Coomassie Plus Protein Assay usingcrystalline bovine serum albumin as a standard (Pierce Chemical Co.,Rockford, Ill.).

[0067] Measurement of PTPase activity: The malachite green-ammoniummolybdate method, as described by Lanzetta P A, Alvarez L J, Reinach PS, Candia O A was used. An improved assay for nanomolar amounts ofinorganic phosphate. Anal. Biochem. 1979;100:95-97, and adapted for theplatereader, is used for the nanomolar detection of liberated phosphateby rat hepatic microsomal PTPases. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). The peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150 and 1151 tyrosine residues. Themicrosomal fraction (83.25 ul) is preincubated for 10 min at 37 deg.Cwith or without test compound (6.25 ul) and 305.5 ul of the 81.83 mMHEPES reaction buffer, pH 7.4. Peptide substrate, 10.5 ul at a finalconcentration of 50 uM, is equilibrated to 37 deg.C in a LABLINEMulti-Blok heater equipped with a titerplate adapter. The preincubatedmicrosomal preparation (39.5 ul) with or without drug is added toinitiate the dephosphorylation reaction, which proceeds at 37 deg.C for30 min. The reaction is terminated by the addition of 200 ul of themalachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).The stopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 ulMG/AM/Tw to substrate and followed by 39.5 ul of the preincubatedmembrane with or without drug. The color is allowed to develop at roomtemperature for 30 min and the sample absorbances are determined at 650nm using a platereader (Molecular Devices). Samples and blanks areprepared in quadruplicates. Screening activity of 50 uM (final) drug isaccessed for inhibition of microsomal PTPases.

[0068] Calculations: PTPase activities, based on a potassium phosphatestandard curve, are expressed as nmoles of phosphate released/min/mgprotein. Test compound PTPase inhibition is calculated as percent ofcontrol. A four parameter non-linear logistic regression of PTPaseactivities using SAS release 6.08, PROC NLIN, is used for determiningIC50 values of test compounds. All compounds were administered at aconcentration of 50 μM. The following results were obtained usingrepresentative compounds of this invention. % Change from ExampleControl 4 −28 6 −30 7 −74 8 −78 9 −20 10 −35 12 −68 15 −47 16 −20 17 −54phenylarsine (Reference) −57

[0069] Inhibition of Tri-Phosphorylated Insulin ReceptorDodecaphosphopeptide Dephosphorylation by hPTP1B

[0070] This standard pharmacological test procedure assess theinhibition of recombinant rat protein tyrosine phosphatase, PTP1B,activity using, as substrate, the phosphotyrosyl dodecapeptidecorresponding to the 1142-1153 insulin receptor kinase domain,phosphorylated on the 1146, 1150 and 1151 tyrosine residues. Theprocedure used and results obtained are briefly described below.

[0071] Human recombinant PTP1B was prepared as described by Goldstein(see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzymepreparation used was in microtubes containing 500-700 μg/ml protein in33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

[0072] Measurement of PTPase activity. The malachite green-ammoniummolybdate method, as described (Lanzetta et al. Anal. Biochem. 100, 95,1979) and adapted for a platereader, is used for the nanomolar detectionof liberated phosphate by recombinant PTP1B. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). the peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150, and 1151 tyrosine residues. Therecombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 mMTris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain anapproximate activity of 1000-2000 nmoles/min/mg protein. The dilutedenzyme (83.25 mL) is preincubated for 10 min at 37° C. with or withouttest compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reactionbuffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50mM, and is equilibrated to 37° C. in a LABLINE Multi-Blok heaterequipped with a titerplate adapter. The preincubated recombinant enzymepreparation (39.5 ml) with or without drug is added to initiate thedephosphorylation reaction, which proceeds at 37° C. for 30 min. Thereaction is terminated by the addition of 200 mL of the malachitegreen-ammoonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). Thestopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mLMG/AM/Tw to substrate and followed by 39.5 ml of the preincubatedrecombinant enzyme with or without drug. The color is allowed to developat room temperature for 30 min. and the sample absorbances aredetermined at 650 nm using a platereader (Molecular Devices). Sample andblanks are prepared in quadruplicates.

[0073] Calculations: PTPase activities, based on a potassium phosphatestandard curve, are expressed as nmoles of phosphate released/min/mgprotein. Inhibition of recombinant PTP1B by test compounds is calculatedas percent of phosphatase control. A four parameters non-linear logisticregression of PTPase activities using SAS release 6.08, PROC NLIN, isused for determining IC₅₀ values of test compounds. The followingresults were obtained. Example IC50 (μM) 1 1.66 2 −47 (2.5 uM) 3 −56(2.5 uM) 5 0.85 6 −47 (2.5 uM) 7 1.29 8 1.25 9 0.65 10 0.47 11 −40 (2.5uM) 12 0.13 13 1.15 14 −65 (2.5 uM) 15 0.93 16 1.2 17 0.98 Phenylarsineoxide 39.7 (reference standard) Sodium orthovanadate 244.8 (referencestandard) Ammonium molybdate 8.7 tetrahydrate (reference standard)

[0074] The blood glucose lowering activity of representative compoundsof this invention were demonstrated in an in vivo standard procedureusing diabetic (ob/ob) mice. The procedures used and results obtainedare briefly described below.

[0075] The non-insulin dependent diabetic (NIDDM) syndrome can betypically characterizes by obesity, hyperglycemia, abnormal insulinsecretion, hyperinsulinemia and insulin resistance. The geneticallyobese-hyperglycemic ob/ob mouse exhibits many of these metabolicabnormalities and is thought to be a useful model to search forhypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14:141-148, 1978].

[0076] In each test procedure, mice [Male or female ob/ob (C57 B1/6J)and their lean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to5 months (10 to 65 g)] of a similar age were randomized according tobody weight into 4 groups of 10 mice. The mice were housed 5 per cageand are maintained on normal rodent chow with water ad libitum. Micereceived test compound daily by gavage (suspended in 0.5 ml of 0.5%methyl cellulose); dissolved in the drinking water; or admixed in thediet. The dose of compounds given ranges from 2.5 to 200 mg/kg bodyweight/day. The dose is calculated based on the fed weekly body weightand is expressed as active moiety.

[0077] The positive control, ciglitazone(5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-dione, see Chang, A., Wyse,B., Gilchrist, B., Peterson, T. and Diani, A. Diabetes 32: 830-838,1983.) was given at a dose of 100 mg/kg/day, which produces asignificant lowering in plasma glucose. Control mice received vehicleonly.

[0078] On the morning of Day 4, 7 or 14 two drops of blood (approximetly50 ul) were collected into sodium fluoride containing tubes either fromthe tail vein or after decapitation. For those studies in which thecompound was administered daily by gavage the blood samples werecollected two hours after compound administration.

[0079] The plasma was isolated by centrifugation and the concentrationof glucose is measured enzymatically on an Abbott V. P. Analyzer.

[0080] For each mouse, the percentage change in plasma glucose on Day 4,7 or 14 is calculated relative to the mean plasma glucose of the vehicletreated mice. Analysis of variance followed by Dunett's Comparison Test(one-tailed) are used to estimate the significant difference between theplasma glucose values from the control group and the individual compoundtreated groups (CMS SAS Release 5.18).

[0081] The results shown in the table below shows that the compounds ofthis invention are antihyperglycemic agents as they lower blood glucoselevels in diabetic mice. % Change Glucose Example Dose (mg/Kg) fromVehicle 5 100 −40^(a) Ciglitazone 100 −43  (reference standard

[0082] Based on the results obtained in the standard pharmacologicaltest procedures, representative compounds of this invention have beenshown to inhibit PTPase activity and lower blood glucose levels indiabetic mice, and are therefore useful in treating metabolic disordersrelated to insulin resistance or hyperglycemia, typically associatedwith obesity or glucose intolerance. More particularly, the compounds ofthis invention useful in the treatment or inhibition of type IIdiabetes, and in modulating glucose levels in disorders such as type Idiabetes. As used herein, the term modulating means maintaining glucoselevels within clinically normal ranges.

[0083] Effective administration of these compounds may be given at adaily dosage of from about 1 mg/kg to about 250 mg/kg, and may given ina single dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, via implants,parenterally (including intravenous, intraperitoneal and subcutaneousinjections), rectally, vaginally, and transdermally. For the purposes ofthis disclosure, transdermal administrations are understood to includeall administrations across the surface of the body and the inner liningsof bodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0084] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0085] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the malady andthe individual being treated and will be subject to the judgment of themedical practitioner involved. It is preferred that the administrationof one or more of the compounds herein begin at a low dose and beincreased until the desired effects are achieved.

[0086] The following procedures describe the preparation ofrepresentative examples of this invention.

EXAMPLE 1

[0087] 4-(4′-Methoxy-biphenyl-4-yl)-5-mehyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0088] Step a) 1-(4-bromo-2-henyl)-propanone oxime

[0089] Sodium acetate (80.0 g, 976 mmol) was added into a mixture of1(4-bromo-phenyl)-propanone (52.0 g, 244 mmol), hydroxylaminehydrochloride (50.8 g, 732.3 mmol), ethyl alcohol (500 mL) and water(100 mL). The reaction mixture was stirred at 60° C. for 1 hour, pouredinto water, and extracted with ethyl ether. The organic extracts weredried over MgSO₄. Evaporation and crystallization from ethylether/hexanes gave a white solid (49.6 g, 89% yield); MS m/e 227(M⁺);Analysis for C₉H₁₀ BrNO: Calc'd: C, 47.39; H, 4.42; N. 6.14 Found: C,47.42; H, 4.37; N, 5.99

[0090] Step b)4-(4-Bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0091] Pyridine (3.55 mL, 43.86 mmol) was added into a mixture of1-(4-bromo-phenyl)-propanone oxime (10.0 g, 43.86 mmol) and toluene (20mL). The reaction mixture was stirred for 30 minutes, and then4-trifluoromethyl-phenyl acetyl chloride (16.27 mL, 109.6 mmol) wasadded dropwise. The new mixture was stirred at 100° C. for 24 hours, andthen w as poured into water and extracted with ethyl acetate. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography on silica gel (hexanes/EtAOc 40:1) gave a whitesolid (7.3 g, 43% yield): mp 82.84° C.; MS m/e 381 (M⁺);

[0092] Analysis for: C₁₇H₁₁BrF₃NO Calc'd: C, 53.43; H, 2.90; N, 3.67Found: C, 53.47; H, 2.62; N, 3.43

[0093] Step c)4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0094] 4-Methoxy-benzeneboronic acid (1.44 g, 7.19 mmol) in ethylalcohol (5 mL) was added into a mixture of4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.5 g,6.54 mmol), sodium carbonate (2N, 6.5 mL),tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.196 mmol), andtoluene (200 mL). The reaction mixture was refluxed for 12 hours, cooledto room temperature, and treated with hydrogen peroxide (30%, 5 mL) for1 hour. Then, the mixture was poured into water and extracted with ethylacetate. The organic extracts were dried over MgSO₄. Evaporation andcrystallization from hexanes/ethyl ether gave a white solid (2.2 g, 82%yield): mp 167-168° C.; MS m/e 409 (M⁺);

[0095] Analysis for: C₂₄H₁₈F₃NO₂ Calc'd: C, 70.41; H, 4.43; N, 3.42Found: C, 70.14; H, 4.32; N, 3.30

EXAMPLE 2

[0096]4-(4′-Methoxy-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0097] The title compound was prepared from4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and4-methoxy-benzeneboronic acid in substantially the same manner, asdescribed in Example 1 step c, and was obtained as a white solid, mp93-94° C.; MS m/e 409 (M⁺);

[0098] Analysis for: C₂₄H₁₈F₃NO₂ Calc'd: C, 70.41; H, 4.43; N, 3.42Found: C, 70.25; H, 4.33; N, 3.34

EXAMPLE 3

[0099]4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0100] Boron tribromide (1.0 M, 3.91 mL, 3.91 mmol) was added dropwiseinto a cold (−78° C.) mixture of4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(1.6 g, 3.91 mmol), and dichloromethane (20 mL). The reaction mixturewas allowed to come gradually to room temperature and stirred for 10hours. Then, the mixture was cooled to 0° C. and methyl alcohol (5 mL)was added dropwise.

[0101] After stirring for 10 minutes the mixture was poured into waterand extracted with ethyl ether. The organic extracts were dried overMgSO₄. Evaporation and crystallization from ethyl ether/hexanes gave anoff-white solid (1.4 g, 90% yield): mp 189-191; MS m/e 396 (M+H)⁺;

[0102] Analysis for: C₂₃H₁₆F₃NO₂ x 0.3H₂O Calc'd: C, 68.92; H, 4.17; N,3.50 Found: C, 68.97; H, 4.23; N, 3.33

EXAMPLE 4

[0103]3′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0104] The title compound was prepared from4-(4′-methoxy-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole,in substantially the same manner, as described in Example 3, and wasobtained as a white solid, mp 133-135° C.; MS m/e 395 (M⁺);

[0105] Analysis for: C₂₃H₁₆F₃NO₂ x 0.3H₂O Calc'd: C, 68.92; H, 4.17; N,3.50 Found: C, 68.98; H, 3.83; N, 3.47

EXAMPLE 5

[0106]{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0107] Sodium hydride (0.05 g, 1.26 mmol) was added into a mixture of4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol(0.5 g, 1.26 mmol), and N,N-dimethylformamide (5.0 mL). The reactionmixture was stirred at room temperature for 1 hour. Methyl bromoacetate(0.18 mL, 1.89 mmol) was added dropwise into the mixture. After stirrngfor 30 minutes, the mixture was poured into water and extracted withethyl acetate. The organic extracts were dried over MgSO₄. Evaporationgave a yellow oil (0.61 g). This residue was taken in methyl alcohol (20mL) and tetrahydrofuran (20 mL), and treated with NaOH (2.5 N, 5.0 mL)for 30 minutes. The new reaction mixture was then poured into water,acidified with HCl (2 N), and extracted with ethyl ether. The organicextracts were dried over MgSO₄. Evaporation and crystallization formhexanes/ethyl ether gave an off-white solid (0.42 g, 73% yield): mp209-211; MS m/e 454 (M+H)⁺;

[0108] Analysis for: C₂₅H₁₈F₃NO₄ Calc'd: C, 66.23; H, 4.00; N, 3.09Found: C, 65.97; H, 3.93; N, 3.04

EXAMPLE 6

[0109]{3′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0110] The title compound was prepared from3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, insubstantially the same manner, as described in Example 6, and wasobtained as a light yellow solid, mp 178-179° C.; MS m/e 453 (M⁺);

[0111] Analysis for: C₂₅H₁₈FNO₄ x 0.3H₂O Calc'd: C, 65.44; H, 3.99; N,3.05 Found: C, 65.50; H, 3.93; N, 2.92

EXAMPLE 7

[0112]2-{4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid

[0113] Diisopropyl azodicarboxylate (0.42 mL, 2.52 mmol) in benzene (10mL) was added dropwise into a cold (0° C.) mixture of4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol(0.5 g, 1.26 mmol), 3-phenyllactic acid methyl ester (0.45 g, 2.52mmol), triphenylphosphine (0.66 g, 2.52 mmol), and benzene (20 mL). Thereaction mixture was stirred at room temperature for 30 minutes, pouredinto water, and extracted with ethyl ether. The organic extracts weredried over MgSO₄. Evaporation gave a yellow oil (0.6 g). This residuewas taken in methyl alcohol (15 mL) and tetrahydrofuran (15 mL) andtreated with sodium hydroxide (2 N, 3.0 mL). The reaction mixture wasstirred for 30 minutes, poured into water, acidified with HCl (2 N), andextracted with ethyl ether. The organic extracts were dried over MgSO₄.Evaporation and crystallization from ethyl ether/hexanes gave a whitesolid (0.38 g, 55% yield): mp 183-184; MS m/e 544 (M+H)⁺;

[0114] Analysis for: C₃₂H₂₄F₃NO₄ Calc'd: C, 70.71; H, 4.45; N, 2.58Found: C, 70.50; H, 4.32; N, 2.53

EXAMPLE 8

[0115]2-{3′-[5-Methyl-2-(4-trifluoromethyl-2-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid

[0116] The title compound was prepared from3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, insubstantially the same manner, as described in Example 7, and wasobtained as a white solid, mp 148-149° C.; MS m/e 543 (M⁺);

[0117] Analysis for: C₃₂H₂₄F₃NO₄ Calc'd: C, 70.71; H, 4.45; N, 2.58Found: C, 70.72; H, 4.28; N, 2.50

EXAMPLE 9

[0118]3,5-Dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol

[0119] Bromine (0.73 mL, 14.18 mmol) in acetic acid (50 mL) was addeddropwise over a 30 minutes period into a cold (5° C.) mixture of4′-(2-benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol (2.8 g, 7.09 mmol),potassium acetate (6.95 g, 70.9 mmol), and acetic acid (200 mL). Afterthe addition, the mixture was poured into water. The precipitated solidwas filtered, washed with water and dried to afford a white solid (2.1g; 61% yield): mp 79-81° C. MS m/e 551 (M⁺);

[0120] Analysis for: C₂₃H₁₄Br₂F₃NO₂ Calc'd: C, 49.94; H, 2.55; N, 2.53Found: C, 49.78; H, 2.46; N, 2.49

EXAMPLE 10

[0121]{3,5-Dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-aceticacid

[0122] The title compound was prepared from3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol,and methyl bromoacetate in substantially the same manner, as describedin Example 5, and was obtained as an off-white solid, mp 165-166° C.; MSm/e 609 (M⁺);

[0123] Analysis for: C₂₅H₁₆Br₂F₃NO₄ Calc'd: C, 49.13; H, 2.64; N, 2.29Found: C, 49.24; H, 2.58; N, 2.16

EXAMPLE 11

[0124]2-{3,5-Dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid methyl ester

[0125] The title compound was prepared from3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol,and 3-phenyllactic acid methyl ester in substantially the same manner,as described in Example 7, and was obtained as a white solid, mp 70-72°C.; MS m/e 713 (M⁺);

[0126] Analysis for: C₃₃H₂₄Br₂F₃NO₄ Calc'd: C, 55.41; H, 3.38; N, 1.96Found: C, 55.01; H, 3.21; N, 1.99

EXAMPLE 12

[0127]2-{3,5-Dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid

[0128] The title compound was prepared from2-{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionicacid methyl ester in substantially the same manner, as described inExample 7, and was obtained as a white solid, mp 241-243° C.; MS m/e 699(M⁺);

[0129] Analysis for: C₃₂H₂₂Br₂F₃NO₄ Calc'd: C, 54.80; H, 3.16; N, 2.00Found: C, 54.54; H, 3.03; N, 2.00

EXAMPLE 13

[0130]2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione

[0131] Step a)4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehyde

[0132] This compound was prepared from4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and4-formylbenzeneboronic acid in substantially the same manner, asdescribed in Example 1 step c, and was obtained as an off-white solid;MS m/e 407 (M⁺);

[0133] Analysis for: C₂₄H₁₆F₃NO₂ Calc'd: C, 70.76; H, 3.96; N, 3.44Found: C, 70.83; H, 3.70; N, 3.42

[0134] Step b)4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehydeoxime

[0135] This compound was prepared from4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehyde,and hydroxylamine in substantially the same manner, as described inExample 1 step a, and was obtained as an off-white solid; MS m/e 422(M⁺);

[0136] Analysis for: C₂₄H₁₇F₃N₂O₂ Calc'd: C, 68.24; H, 4.06; N, 6.63Found: C, 68.10; H, 3.82; N, 6.45

[0137] Step c)N-{4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine

[0138] Hydrochloric acid (4 N, in dioxane, 10 mL) was added dropwiseinto a mixture of4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-carbaldehydeoxime (1.5 g, 3.56 mmol), sodium cyanoborohydride (1.1 g, 17.81 mmol),methyl alcohol (100 mL), and tetrahydrofuran (100 mL). The reactionmixture was stirred for 1 hour poured into water, basified with sodiumhydroxide (2 N), and extracted with ethyl acetate. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (EtOAc/MeOH 20:1) gave an off-white solid(1.21 g, 80% yield); MS m/e 424 (M⁺);

[0139] Analysis for: C₂₄H₁₉F₃N₂O₂ x H₂O Calc'd: C, 67.06; H, 4.60; N,6.52 Found: C, 67.10; H, 4.34; N, 6.69

[0140] Step d)2-{4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-[1,2,4]-oxadiazolidine-3.5-dione

[0141] N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was addeddropwise into a cold (−5° C.) mixture ofN-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine(1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL). The reaction mixture wasstirred for 30 minutes, poured into water, acidified with HCl (2 N), andextracted with ethyl acetate. The organic extracts were dried overMgSO₄. Evaporation and purification by flash chromatography on acidicsilica gel (hexanes/EtOAc 2:1) gave a white solid (0.68 g, 53% yield):mp 196-198; MS m/e 493 (M⁺);

[0142] Analysis for: C₂₆H₁₈F₃N₃O₄ Calc'd: C, 63.29; H, 3.68; N, 8.52Found: C, 62.95; H, 3.51; N, 8.40

EXAMPLE 14

[0143]2-{4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-3-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione

[0144] This compound was prepared from3-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole insubstantially the same manner, as described in Example 1 steps a-d, andwas obtained as a white solid, mp 216-218; MS m/e 493 (M⁺);

[0145] Analysis for: C₂₆H₁₈F₃N₃O₄ Calc'd: C, 63.29; H, 3.68; N, 8.52Found: C, 63.23; H, 3.43; N, 8.48

EXAMPLE 15

[0146]5-{4′-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxymethy}-1H-tetrazole

[0147] Sodium hydride (0.1 g, 2.52 mmol) was added into a mixture of4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol(1.0 g, 2.52 mmol), and N,N-dimethylformamide (5.0 mL). The reactionmixture was stirred at room temperature for 1 hour. Methylbromoacetonitrile (0.17 mL, 2.52 mmol) was added dropwise into themixture. After stirring for 30 minutes, the mixture was poured intowater and extracted with ethyl acetate. The organic extracts were driedover MgSO₄. Evaporation gave a yellow oil (1.1 g). This residue wastaken in N,N-dimethylformamide (20 mL), and treated with ammoniumchloride (0.67 g, 12.6 mmol), and sodium azide (0.82 g, 12.6 mmol) at120° C. for 10 hours. The mixture was then poured into water, acidifiedwith HCl (2 N), and extracted with ethyl ether. The organic extractswere dried over MgSO₄. Evaporation and crystallization form hexanes tethyl ether gave a white solid (0.49 g, 41% yield): mp 226-227; MS m/e477 (M⁺);

[0148] Analysis for: C₂₅H₁₈F₃N₅O₂ Calc'd: C, 62.89; H, 3.80; N, 14.67Found: C, 62.54; H, 3.63; N, 14.76

EXAMPLE 16

[0149]{1-Bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-naphthalen-2-yloxy}-aceticacid

[0150] Step a)4′-(6-Methoxy-naphthalen-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole

[0151] This compound was prepared from1-(6-methoxy-naphthalen-2-yl)propanone oxime, and4-trifluoromethyl-phenyl acetyl chloride in substantially the samemanner, as described in Example 1 steps b, and was obtained as a whitesolid, mp 138-139; MS m/e 383 (M⁺);

[0152] Analysis for: C₂₂H₁₉F₃NO₂ Calc'd: C, 68.93; H, 4.21; N, 3.65Found: C, 68.83; H, 4.25; N, 3.70

[0153] Step b)6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-naphthalen-2-ol

[0154] This compound was prepared from4′-(6-methoxy-naphthalen-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoleand boron tribromide in substantially the same manner, as described inExample 3, and was obtained as a white solid, mp 188-191; MS m/e 370(M+H)⁺;

[0155] Analysis for: C₂₁H₁₄F₃NO₂ Calc'd: C, 68.29; H, 3.82; N, 3.79Found: C, 67.81; H, 3.76; N, 3.66

[0156] Step c)1-Bromo-6-[5-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-naphthalen-2-ol

[0157] This compound was prepared from4′-(6-hydroxy-naphthalen-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoleand bromine in substantially the same manner, as described in Example 9,and was obtained as an off-white solid; MS m/e 447 (M⁺); Analysis for:C₂₁H₁₃BrF₃NO₂ Calc'd: C, 56.27; H, 2.92; N, 3.12 Found: C, 56.20; H,2.66; N, 3.15

[0158] Step d){1-Bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-naphthalen-2-yloxy}-aceticacid

[0159] This compound was prepared from4′-(5-bromo-6-hydroxy-naphthalen-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoleand methyl bromoacetate in substantially the same manner, as describedin Example 5, and was obtained as white solid, mp 212-214° C.; MS m/e506 (M+H)⁺;

[0160] Analysis for: C₂₃H₁₅BrF₃NO₄ Calc'd: C, 54.57; H, 2.99; N, 2.77Found: C, 54.17; H, 2.69; N, 2.76

EXAMPLE 17

[0161]2-{1-Bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-naphthalen-2-yloxy}-3-phenyl-propionicacid

[0162] This compound was prepared from4′-(5-bromo-6-hydroxy-naphthalen-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoleand methyl bromoacetate in substantially the same manner, as describedin Example 7, and was obtained as an off-white solid, mp 195-197° C.; MSm/e 596 (M+H)⁺;

[0163] Analysis for: C₃₀H₂₁BrF₃NO₄ Calc'd: C, 60.42; H, 3.55; N, 2.35Found: C, 60.31; H, 3.35; N, 2.42

What is claimed is:
 1. A compound of formula I having the structure

wherein

R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,

R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms; R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹, —C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹°, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰, —CH(R⁸)C₆H₄CO₂R¹⁰, or —CH₂-tetrazole; R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms; R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,

R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²; R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; R¹¹ is alkylene of 1 to 3 carbon atoms; R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; X is O, or S; Y is O, N, or S; Z is C, or N; Q is O, N, or S; m=1-3; n=1-6, or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein X is oxygen, or a pharmaceutically acceptable salt thereof.
 3. The compound according to claim 2, wherein R¹ is phenyl substituted with R⁶; R² is alkyl of 1-6 carbon atoms; and R³ and R⁴ are each, independently, hydrogen or halogen. or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 which is 4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 which is 4-(4′-methoxy-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1 which is 4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-ol or a pharmaceutically acceptable salt thereof.
 7. The compound of claim 1 which is 3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 1 which is {4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-acetic acid or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 1 which is {3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-acetic acid or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 1 which is 2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 1 which is 2-{3′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.
 12. The compound of claim 1 which is 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol or a pharmaceutically acceptable salt thereof.
 13. The compound of claim 1 which is {3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-acetic acid or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1 which is 2-{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionic acid methyl ester or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1 which is 2-{3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 1 which is 2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof.
 17. The compound of claim 1 which is 2-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-3-ylmethyl}-[1,2,4]oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof.
 18. The compound of claim 1 which is 5-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxymethyl}-1H-tetrazole or a pharmaceutically acceptable salt thereof.
 19. A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

wherein

R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,

R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms; R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atom's, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹, —C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹⁰, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰, —CH(R⁸)C₆H₄CO₂R¹⁰, or —CH₂-tetrazole; R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms; R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,

R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²; R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; R¹¹ is alkylene of 1 to 3 carbon atoms; R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; X is O, or S; Y is O, N, or S; Z is C, or N; Q is O, N, or S; m=1-3; n=1-6, or a pharmaceutically acceptable salt thereof.
 20. A method of treating or inhibiting type II diabetes in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

wherein

R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,

R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms; R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹, —C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹⁰, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰, —CH(R⁸)C₆H₄CO₂R¹⁰, or —CH₂-tetrazole; R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms; R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,

R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²; R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; R¹¹ is alkylene of 1 to 3 carbon atoms; R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; X is O, or S; Y is O, N, or S; Z is C, or N; Q is O, N, or S; m=1-3; n=1-6, or a pharmaceutically acceptable salt thereof.
 21. A method of modulating glucose levels in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure

wherein

R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,

R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms; R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹, —C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹⁰, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰, —CH(R⁸)C₆H₄CO₂R¹⁰, or —CH₂-tetrazole; R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms; R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,

R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²; R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; R¹¹ is alkylene of 1 to 3 carbon atoms; R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; X is O, or S; Y is O, N, or S; Z is C, or N; Q is O, N, or S; m=1-3; n=1-6, or a pharmaceutically acceptable salt thereof.
 22. A pharmaceutical composition which comprises a compound of formula I having the structure

wherein

R¹ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl,

R² is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6 to 10 carbon atoms; R³ and R⁴ are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6 to 10 carbon atoms; halogen, trifluoromethylof 1-6 carbon atoms, alkoxyaryl of 7-14 carbon atoms; nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, —NR⁷(CH₂)_(m)CO₂H, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, or heterocycle of 5 to 7 atom rings containing from 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁸)R⁹, —C(CH₂)_(n)CO₂R¹⁰, —C(CH₃)₂CO₂R¹°, —CH(R⁸)(CH₂)_(n)CO₂R¹⁰, —CH(R⁸)C₆H₄CO₂R¹ 0, or —CH₂-tetrazole; R⁶ is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkyoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkoxy of 1-6 carbon atoms; R⁷ is hydrogen or alkyl of 1 to 6 carbon atoms; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid,

R⁹ is CO₂R¹², CONHR¹², tetrazole, PO₃R¹²; R¹⁰ is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; R¹¹ is alkylene of 1 to 3 carbon atoms; R¹² is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms; X is O, or S; Y is O, N, or S; Z is C, or N; Q is O, N, or S; m=1-3; n=1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. 